CN104055739A - Method for preparing tebipenem pivoxil composition granules - Google Patents
Method for preparing tebipenem pivoxil composition granules Download PDFInfo
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- CN104055739A CN104055739A CN201410320853.3A CN201410320853A CN104055739A CN 104055739 A CN104055739 A CN 104055739A CN 201410320853 A CN201410320853 A CN 201410320853A CN 104055739 A CN104055739 A CN 104055739A
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Abstract
The invention relates to the technical field of medicines and discloses a method for preparing tebipenem pivoxil composition granules. The preparation method comprises the following step of performing wet granulation on medicinal components such as tebipenem pivoxil, cane sugar, hydroxyethyl methylcellulose, croscarmellose sodium, phosphatidyl ethanolamine, inositol, sodium ascorbate palmitate and aspartame to obtain the tebipenem pivoxil composition granules. According to the preparation method, a novel granule is prepared by adopting multiple proper medicinal components comprising tebipenem pivoxil through wet granulation. The prepared granules have the effects superior to those of existing patented products in acceleration test, long-term test and antibacterial effect test, have extremely high quality and can be widely applied to clinical treatment.
Description
Technical field
The present invention relates to field of medicine preparations, be specifically related to a kind of preparation method of L-084 composition granule.
Background technology
L-084, chemistry (+)-(4R by name, 5S, 6S)-6-[(1R)-hydroxyethyl]-4-methyl-7-oxo-3[[1-(2-thiazoline-2-yl)-3-azetidinyl] sulfur]-1-azabicyclo [3.2.0] hept-2-ene"-2-formic acid (2,2-dimethyl-1-oxopropoxy) methyl ester, belong to carbapenem antibiotic, structural formula is as follows:
L-084 is researched and developed by Pfizer Inc. the earliest, and L-084 granula subtilis is developed by Japanese Mingzhi company, obtains Japan's approval in February, 2009, and in April, 2009 listing, but does not domesticly have listing producer and a relevant report.L-084 granula subtilis is for the treatment of pediatric patient otorhinolaryngology and upper respiratory tract infection, and it is first treatment of infecting for streptococcus pneumoniae drug resistance strain, comprises the penem-like pharmaceutical of persistence otitis media and bacterial pneumonia.L-084 has a broad antifungal spectrum, bacterial strain to most of clinical separation, tebipenem all shows than penicillin series and the stronger antibiotic property of cephalo series, and compares with the carbapenem antibiotic of other injections, and tebipenem also shows same degree or stronger antibacterial effect.Particularly for causing in recent years that the penicillin resistance pneumococcus of childhood infection main cause, resistance to erythromycin streptococcus pneumoniae and hemophilus influenza showed extremely strong antibacterial effect.
Due to L-084 less stable, under hot and humid condition related substance increase very large, so that the selection of the selection of ingredient and consumption and preparation method becomes is particularly important.In view of the reason of L-084 less stable, existing preparation method is mostly selected dry granulation, the impact of avoiding method as this in wet granulation to bring, but the yield of dry granulation is low compared with wet granulation.
Meanwhile, ingredient chooses at random and also likely makes L-084 granule dissolution variation, related substance increase, content minimizing, polymer increase, moisture rising etc., even cannot granulating.Application number is that 201310493646.3 Chinese patent discloses a kind of L-084 composition granule, it be take L-084, pregelatinized Starch, mannitol, sucrose and stevioside and makes as component, although long term test and accelerated test result that this patent is recorded show that this granule has certain quality, but aspect L-084 granule quality, still need further to be improved.In addition, the selection of ingredient also affects the fungistatic effect of L-084, by selecting appropriate ingredient to make a kind of stability and fungistatic effect, higher than the L-084 granule of existing product, is how medical research staff's research emphasis.
Summary of the invention
In view of this, the object of the present invention is to provide a kind of preparation method of L-084 composition granule, make the granule of preparing by wet granulation there is higher stability at extreme environment;
Another object of the present invention is to provide a kind of preparation method of L-084 composition granule, and the fungistatic effect of prepared granule is improved.
For achieving the above object, the invention provides following technical scheme:
A kind of preparation method of L-084 granule, in weight portion, by the L-084 of ingredient 40 weight portions, 198.7-219.7 the sucrose of weight portion, 5-10 weight portion hydroxyethylmethyl-cellulose, 3-6 weight portion cross-linking sodium carboxymethyl cellulose, 2-5 weight portion PHOSPHATIDYL ETHANOLAMINE, 10-20 weight portion inositol and 0.1-0.2 weight portion sodium ascorbate cetylate join in high-speed mixing granulating machine, after being dry mixed evenly, add appropriate dehydrated alcohol, stir cutting soft material processed, with nylon wire, carry out swing granulation, the wet grain of gained is dried to moisture and is not more than 1.5%, then screening, add ingredient 0.2-0.5 weight portion aspartame always mixed, obtain described granule.
The present patent application people furthers investigate physicochemical property, stability feature and the granule formulation characteristic of L-084, according to these features, selects the collaborative L-084 of suitable ingredient to adopt wet granulation to make novel particle agent.
Wherein, as preferably, each ingredient parts by weight are:
The sucrose of the L-084 of 40 weight portions, 209 weight portions, 7.5 weight portion hydroxyethylmethyl-celluloses, 4.5 weight portion cross-linking sodium carboxymethyl celluloses, 3.5 weight portion PHOSPHATIDYL ETHANOLAMINE, 15 weight portion inositols, 0.15 weight portion sodium ascorbate cetylate, 0.35 weight portion aspartame.
As preferably, the ambient humidity of described preparation process is below 60%.
As preferably, the powder particle diameter of described each ingredient is 80 orders.
As preferably, described nylon wire adopts 16 order mesh screens.
As preferably, described screening for shaking screen, sieve out between 16 orders and 60 orders tiny evenly, without the granule of bulk.
As preferably, described dry referring to adopts 18 ℃ of-30 ℃ of vacuum dryings.
The accelerated test of the granule that the present invention is prepared and long-term test results demonstration, the patent that is all 201310493646.3 than application number on the total impurities content in same stage is less, has significant difference.Meanwhile, in the detection of antibacterial activity, the antibacterial effect of granule of the present invention is improved, its MIC
50and MIC
90the data that (minimum inhibitory concentration that suppresses 50% and 90% bacterial strain) all recorded lower than 201310493646.3 patents.
From above technical scheme, preparation method of the present invention adopts the multiple suitable drugs composition that comprises L-084 to adopt wet granulation to prepare a kind of new granule, prepared granule all shows the effect higher than existing patented product in accelerated test, long term test and fungistatic effect test, there is very high quality, can be widely used in clinical treatment.
The specific embodiment
The invention discloses a kind of preparation method of L-084 composition granule, those skilled in the art can use for reference content herein, suitably improve technological parameter and realize.Special needs to be pointed out is, all similar replacements and change apparent to those skilled in the artly, they are all deemed to be included in the present invention.Preparation method of the present invention is described by preferred embodiment, related personnel obviously can be within not departing from content of the present invention, spirit and scope to compound as herein described with preparation method is changed or suitably change and combination, realize and apply the technology of the present invention.
Below in conjunction with embodiment, further set forth the present invention.
Embodiment 1: the preparation of L-084 composition granule
At relative humidity, be under the environment below 60%, by the L-084 of ingredient 40 weight portions, the sucrose of 209 weight portions, 7.5 weight portion hydroxyethylmethyl-celluloses, 4.5 weight portion cross-linking sodium carboxymethyl celluloses, 3.5 weight portion PHOSPHATIDYL ETHANOLAMINE, 15 weight portion inositols, 0.15 weight portion sodium ascorbate cetylate joins in high-speed mixing granulating machine, after being dry mixed evenly, add appropriate dehydrated alcohol, stir cutting soft material processed, with 16 order nylon wires, carry out swing granulation, 24 ℃ of vacuum drying to moisture of the wet grain of gained are not more than 1.5%, then with shaking screen sieve out between 16 orders and 60 orders tiny evenly, granule without bulk, add ingredient 0.35 weight portion aspartame always mixed, obtain described granule.
Embodiment 2: the preparation of L-084 composition granule
At relative humidity, be under the environment below 60%, by the L-084 of ingredient 40 weight portions, 219.7 the sucrose of weight portion, 5 weight portion hydroxyethylmethyl-celluloses, 3 weight portion cross-linking sodium carboxymethyl celluloses, 2 weight portion PHOSPHATIDYL ETHANOLAMINE, 10 weight portion inositols, 0.1 weight portion sodium ascorbate cetylate joins in high-speed mixing granulating machine, after being dry mixed evenly, add appropriate dehydrated alcohol, stir cutting soft material processed, with 16 order nylon wires, carry out swing granulation, 18 ℃ of vacuum drying to moisture of the wet grain of gained are not more than 1.5%, then with shaking screen sieve out between 16 orders and 60 orders tiny evenly, granule without bulk, add ingredient 0.2 weight portion aspartame always mixed, obtain described granule.
Embodiment 3: the preparation of L-084 composition granule
At relative humidity, be under the environment below 60%, by the L-084 of ingredient 40 weight portions, 198.7 the sucrose of weight portion, 10 weight portion hydroxyethylmethyl-celluloses, 6 weight portion cross-linking sodium carboxymethyl celluloses, 5 weight portion PHOSPHATIDYL ETHANOLAMINE, 20 weight portion inositols, 0.2 weight portion sodium ascorbate cetylate joins in high-speed mixing granulating machine, after being dry mixed evenly, add appropriate dehydrated alcohol, stir cutting soft material processed, with 16 order nylon wires, carry out swing granulation, 30 ℃ of vacuum drying to moisture of the wet grain of gained are not more than 1.5%, then with shaking screen sieve out between 16 orders and 60 orders tiny evenly, granule without bulk, add ingredient 0.5 weight portion aspartame always mixed, obtain described granule.
Embodiment 4: accelerated test
The L-084 composition granule of the embodiment of the present invention 1 preparation is known to the relevant regulations of principle according to Chinese Pharmacopoeia version medicine stability test in 2005, under being 40 ℃ ± 2 ℃, the condition of relative humidity 75% ± 5%, temperature carries out accelerated test, time is 6 months, duration of test respectively at the 1st, 2,3,6 samplings at the end of month once, by stability high spot reviews project, measure, the results are shown in Table 1.
Table 1 accelerated test result
The testing result of table in reference, and the Data Comparison recorded of application number patent working example 4 tables 5 that are 201310493646.3, can obviously find out, aspect impurity content, the present invention has reduced by 0.17% left and right, has further improved the stability of product.
Embodiment 5: long term test
The L-084 composition granule of the embodiment of the present invention 1 preparation is known to the relevant regulations of principle according to Chinese Pharmacopoeia version medicine stability test in 2005, under being 25 ℃ ± 2 ℃, the condition of relative humidity 60% ± 10%, temperature carries out accelerated test, time is 36 months, duration of test respectively at the 0th, 3,6,9,12,18,24,36 samplings at the end of month once, by stability high spot reviews project, measure, the results are shown in Table 2.
Table 2 long-term test results
The testing result of table in reference, and the Data Comparison recorded of application number patent working example 4 tables 6 that are 201310493646.3, can obviously find out, aspect impurity content, the present invention has reduced by 0.17% left and right, has further improved the stability of product.
Embodiment 6: fungistatic effect test
Adopt agar dilution to measure the minimum inhibitory concentration of the embodiment of the present invention 1 L-084 composition granule, with the inoculation of multiple spot dibbler, each point is approximately containing 10
4cFU, cultivates 24h, the results are shown in Table 3 for 37 ℃.
The test of table 3 fungistatic effect
As seen from the above table, preparation method of the present invention is owing to selecting suitable drug composition, can bring into play to greatest extent the fungistatic effect of L-084, contrast granule (the patent working example 3 that data are 201310493646.3 with reference to application number is recorded) is apparently higher than MIC of the present invention
50and MIC
90, fungistatic effect is not as granule of the present invention.
The above is only the preferred embodiment of the present invention; it should be pointed out that for those skilled in the art, under the premise without departing from the principles of the invention; can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.
Claims (7)
1. the preparation method of a L-084 composition granule, it is characterized in that, in weight portion, by the L-084 of ingredient 40 weight portions, 198.7-219.7 the sucrose of weight portion, 5-10 weight portion hydroxyethylmethyl-cellulose, 3-6 weight portion cross-linking sodium carboxymethyl cellulose, 2-5 weight portion PHOSPHATIDYL ETHANOLAMINE, 10-20 weight portion inositol and 0.1-0.2 weight portion sodium ascorbate cetylate join in high-speed mixing granulating machine, after being dry mixed evenly, add appropriate dehydrated alcohol, stir cutting soft material processed, with nylon wire, carry out swing granulation, the wet grain of gained is dried to moisture and is not more than 1.5%, then screening, add ingredient 0.2-0.5 weight portion aspartame always mixed, obtain described granule.
2. preparation method according to claim 1, is characterized in that, described each ingredient parts by weight are:
The sucrose of the L-084 of 40 weight portions, 209 weight portions, 7.5 weight portion hydroxyethylmethyl-celluloses, 4.5 weight portion cross-linking sodium carboxymethyl celluloses, 3.5 weight portion PHOSPHATIDYL ETHANOLAMINE, 15 weight portion inositols, 0.15 weight portion sodium ascorbate cetylate, 0.35 weight portion aspartame.
3. preparation method according to claim 1, is characterized in that, the ambient humidity of described preparation process is below 60%.
4. preparation method according to claim 1, is characterized in that, the powder particle diameter of described each ingredient is 80 orders.
5. preparation method according to claim 1, is characterized in that, described nylon wire adopts 16 order mesh screens.
6. preparation method according to claim 1, is characterized in that, described screening for shaking screen, sieve out between 16 orders and 60 orders tiny evenly, without the granule of bulk.
7. preparation method according to claim 1, is characterized in that, described dry referring to adopts 18 ℃ of-30 ℃ of vacuum dryings.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201410320853.3A CN104055739B (en) | 2014-07-07 | 2014-07-07 | Method for preparing tebipenem pivoxil composition granules |
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| CN201410320853.3A CN104055739B (en) | 2014-07-07 | 2014-07-07 | Method for preparing tebipenem pivoxil composition granules |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2004035517A (en) * | 2002-07-08 | 2004-02-05 | Wyeth Lederle Japan Ltd | Carbapenem antibiotic-containing oral preparation |
| CN103371977A (en) * | 2012-04-25 | 2013-10-30 | 秦引林 | Tebipenem ester particles and preparation method thereof |
| CN103520120A (en) * | 2013-10-17 | 2014-01-22 | 山东罗欣药业股份有限公司 | Tebipenam pivoxil composition granule |
-
2014
- 2014-07-07 CN CN201410320853.3A patent/CN104055739B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2004035517A (en) * | 2002-07-08 | 2004-02-05 | Wyeth Lederle Japan Ltd | Carbapenem antibiotic-containing oral preparation |
| CN103371977A (en) * | 2012-04-25 | 2013-10-30 | 秦引林 | Tebipenem ester particles and preparation method thereof |
| CN103520120A (en) * | 2013-10-17 | 2014-01-22 | 山东罗欣药业股份有限公司 | Tebipenam pivoxil composition granule |
Non-Patent Citations (2)
| Title |
|---|
| 罗明生等: "《药剂辅料大全》", 31 January 2006, 四川科学技术出版社 * |
| 迟玉杰: "《食品添加剂》", 30 April 2013, 中国轻工业出版社 * |
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